Biology subjects

Maier, K.

Publications and source records attributed to Maier, K..

8 recordsLinked to original sources

bioRxiv2026

A human immune system mouse model for preclinical evaluation of therapies in pemphigoid disease

Pemphigoid diseases (PD) including Epidermolysis bullosa acquisita (EBA) are rare immunoglobulin G (IgG)-driven autoimmune skin blistering diseases with limited therapeutic options. Mechanistically, chronic inflammation in the skin leads to disruption of the dermal-epidermal junction (DEJ) with a crucial contribution of Fc{gamma}R-mediated activation of myeloid immune cells such as neutrophils. Thus, targeting of kinases involved in Fc{gamma}R-dependent activation of myeloid immune cells holds great promise as a therapeutic strategy. In this study, we employ human immune system (HIS) mice featuring all major human leukocytes which allows to investigate the impact of therapeutics on human immune cells in vivo. In a passive transfer approach, repetitive application of collagen VII (COL7c) specific IgG was associated with skin inflammation including infiltration of activated human immune cells and thickening of the epidermis. While application of recombinant human G-CSF boosted myeloid cell maturation and thus disease severity, treatment with Fc{gamma}R-blocking antibodies impaired disease development confirming the crucial role of human cells. Finally, small molecule PDK1 inhibitor BX-795 abrogated development of skin inflammation associated with reduced leukocyte infiltration and activation supporting the role of PDK1 in Fc{gamma}R-driven immune cell activation. This study establishes the first in vivo model of EBA in HIS mice and reveals its suitability for pre-clinical screening and evaluation of therapeutic agents. Importantly, it highlights the potential of kinase inhibition for treatment of EBA.

immunology↗

bioRxiv2026

Different modes of engagement with the nucleosome acidic patch yield distinct functional outcomes

The nucleosome acidic patch is a hub of coordinated engagement by proteins that regulate genomic function. Here we report that S. cerevisiae Dot5 contains an arginine-rich HMGN-like motif that mediates nucleosome acidic patch binding and is required for the cell growth, DNA repair and heterochromatin defects exhibited when the protein is overexpressed. The heterologous expression of camelid single chain antibodies to the nucleosome acidic patch confers a similar range of phenotypes, with the most severe observed when an arginine-anchor mode of binding analogous to many endogenous factors is employed. This highlights a delicate balance between nucleosome acidic patch interactors critical for normal cellular functions and dysregulated in disease.

molecular biology↗

bioRxiv2025

Structure of a transcribing Pol II-DSIF-SPT6-U1 snRNP complex

RNA polymerase II (Pol II) facilitates co-transcriptional splicing by recruiting the U1 small nuclear ribonucleoprotein particle (U1 snRNP) to the nascent transcripts. Here, we report the cryo-electron microscopy structure of a transcribing Pol II-U1 snRNP complex with elongation factors DSIF and SPT6. Furthermore, our biochemical analysis revealed that the phosphorylated Pol II carboxyl-terminal domain and SPT6 interact directly with U1 snRNP proteins, facilitating its recruitment to the elongation complex. This multivalent interaction allows efficient spliceosome assembly and ensures transcription processivity.

molecular biology↗

bioRxiv2024

Visual circuitry for distance estimation in Drosophila

Animals must infer the three-dimensional structure of their environment from two-dimensional images on their retinas. In particular, visual cues like motion parallax and binocular disparity can be used to judge distances to objects. Studies across several animal models have found neural signals that correlate with visual distance, but the causal role of these neurons in distance estimation as well as the range of possible neural properties that can inform distance estimation have remained poorly understood. Here, we developed a novel high-throughput behavioral assay to identify neurons in the Drosophila visual system that are involved in distance estimation during free locomotion. We found that silencing the primary motion detectors in the fly visual system eliminated their ability to perceive distance, consistent with a reliance on motion parallax to judge distance. Through a targeted silencing screen of visual neurons during behavior and through in vivo two-photon microscopy, we identified a visual projection neuron that encodes the parallax signal in the relative motion of foreground and background. Interestingly, it differs from previously identified parallax-tuned neurons in its lack of direction selectivity both to moving bars and to moving backgrounds. This non-canonical tuning is interpretable in the context of parallax signals that the fly would likely encounter during naturalistic walking behavior. Our results demonstrate how both direction selective and non-direction selective feature-detecting neurons can contribute to distance estimation using parallax cues, providing a framework for considering broader classes of parallax-encoding neurons in distance estimation across visual systems.

neuroscience↗

bioRxiv2023

Neural circuit mechanisms underlying context-specific halting in Drosophila.

Walking is a complex motor program involving coordinated and distributed activity across the brain and the spinal cord. Halting appropriately at the correct time is a critical but often overlooked component of walking control. While recent studies have delineated specific genetically defined neuronal populations in the mouse brainstem that drive different types of halting1-3, the underlying neural circuit mechanisms responsible for overruling the competing walking-state neural activity to generate context-appropriate halting, remain unclear. Here, we elucidate two fundamental mechanisms by which Drosophila implement context-appropriate halting. The first mechanism ("walk-OFF" mechanism) relies on GABAergic neurons that inhibit specific descending walking commands in the brain, while the second mechanism ("brake" mechanism) relies on excitatory cholinergic neurons in the nerve-cord that lead to an active arrest of stepping movements. Using connectome-informed models4-6 and functional studies, we show that two neuronal types that deploy the "walk-OFF" mechanism inhibit distinct populations of walking-promotion neurons, leading to differential halting of forward-walking or steering. The "brake" neurons on the other hand, override all walking commands by simultaneously inhibiting descending walking promoting pathways and increasing the resistance at the leg-joints leading to an arrest of leg movements in the stance phase of walking. We characterized two ethologically relevant behavioral contexts in which the distinct halting mechanisms were used by the animal in a mutually exclusive manner: the "walk-OFF" pathway was engaged for halting during feeding, and the "brake" pathway was engaged for halting during grooming. Furthermore, this knowledge of the neural targets and mechanisms for halting, allowed us to use connectomics to predict novel halting pathways that could be relevant in other behavioral contexts.

neuroscience↗

bioRxiv2022

Insights from CRISPR/Cas9-mediated gene editing of centromeric histone H3 (CENH3) in carrot (Daucus carota subsp. sativus)

The generation of haploids is one of the most powerful means to accelerate the plant breeding process. In most crop species, an efficient haploid technology is not yet available or only applicable to a limited set of genotypes. Recent results published for Arabidopsis thaliana and major cereal crops like maize and wheat about successful haploid induction by CRISPR/Cas9-mediated editing of the centromeric histone H3 gene (CENH3) suggest that this novel method for the production of haploid plants might also be applicable to vegetable species like carrot. Here, we report and summarize the different experimental and genetic approaches that have been focused in the past few years on CRISPR/Cas9-based editing of the carrot CENH3 gene. We also describe the discovery of a second CENH3 locus in the carrot genome, which complicates the attempts to generate and to analyse putative haploid inducer genotypes. We show that three different CRISPR/Cas9 target constructs, used alone or in combinations, could successfully target carrot CENH3. Promising mutants such as in-frame indel or in-frame deletion mutants have been found, but their successful usage as putative haploid inducer is uncertain yet. Next generation sequencing of amplicons spanning CRISPR target sites and transcript-based amplicon sequencing seemed to be appropriate methods to select promising mutants, to estimate mutation frequencies, and to allow a first prediction which gene was concerned. Another aim of this study was the simultaneous knockout and complementation of the endogenous carrot CENH3 gene by an alien CENH3 gene. Co-transformation of a CRISPR/Cas9-based carrot CENH3 knockout construct together with a CENH3 gene cloned from ginseng (Panax ginseng) was performed by using Rhizobium rhizogenes. It was shown, that ginseng CENH3 protein is accumulated inside the kinetochore region of carrot chromosomes, indicating that PgCENH3 might be a suited candidate for this approach. However, presently it is unclear, if this gene is fully functioning during the meiotic cell divisions and able to complement lethal gametes. Challenges and future prospects to develop a CENH3-based HI system for carrot are discussed.

plant biology↗

bioRxiv2021

Svep1 stabilizes developmental vascular anastomosis in reduced flow conditions.

We report the discovery that flow and Svep1 are modulator of vessel anastomosis during developmental angiogenesis in zebrafish embryos. We show that loss of Svep1 and blood flow reduction both contribute to defective anastomosis of intersegmental vessels. We show that this defect in primary angiogenic sprouts is associated with an expansion of Apelin-positive tip cells and with reduced formation and lumenisation of the dorsal longitudinal anastomotic vessel. Mechanistically, our results suggest that flow and Svep1 act synergistically to modulate vascular network formation in the zebrafish trunk.

developmental biology↗

bioRxiv2020

Recovery of Consciousness and Cognition after General Anesthesia in Humans

Understanding how consciousness and cognitive function return after a major perturbation is important clinically and neurobiologically. To address this question, we conducted a three-center study of 30 healthy humans receiving general anesthesia at clinically relevant doses for three hours. We administered a pre- and post-anesthetic battery of neurocognitive tests, recorded continuous electroencephalography to assess cortical dynamics, and monitored sleep-wake activity before and following anesthetic exposure. We hypothesized that cognitive reconstitution would be a process that evolved over time in the following sequence: attention, complex scanning and tracking, working memory, and executive function. Contrary to our hypothesis, executive function returned first and electroencephalographic analyses revealed that frontal cortical dynamics recovered faster than posterior cortical dynamics. Furthermore, actigraphy indicated normal sleep-wake patterns in the post-anesthetic period. These recovery patterns of higher cognitive function and arousal states suggest that the healthy human brain is resilient to the effects of deep general anesthesia.

neuroscience↗